1. Field of the Invention
The field of the present invention relates to methods and compositions for reducing side effects HMG-CoA reductase inhibitor therapy particularly those related to the physiologically depressed levels of coenzyme Q.sub.10 in the animal. Most particularly, the invention provides methods effective for the reduction of cholesterol using an HMG-CoA reductase inhibitor, while reducing and/or inhibiting the side effects clinically linked to the use of HMG-CoA reductase inhibitors, such as liver dysfunction, musculoskeletal, nervous system/psychiatric, cardiac dysfunction, skin and special senses disorders. The invention also provides specifically defined formulations which include a mixture of an HMG-CoA reductase inhibitor and coenzyme Q.sub.10.
2. Description of the Related Art
Coronary artery disease is the major cause of death in Western countries. Hypercholesterolemia is known to be a primary risk factor for death from coronary artery disease. It is known that 50% or more of the total body cholesterol in humans is derived from intrinsic biosynthesis. It is also known that a rate-limiting step of major significance in the biosynthesis of cholesterol is at the level of the enzyme known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase or HMG-CoA reductase. This enzyme then was logical for inhibition to reduce the intrinsic biosynthesis of cholesterol toward reducing the risk factor of hypercholesterolemia and coronary artery death.
Alberts et al. described the isolation, structure and biochemical properties of an active inhibitor of HGMCoA reductase which they named mevinolin. The scientific name, mevinolin, introduced in 1980, corresponds to the subsequent trademark name, MEVACOR.RTM.. This chemical substance is 1,2,6,7,8,8a-hexahydro-.beta.,.delta.-dihydroxy-2,6-dimethyl-8-(2-methyl-1 -oxobutoxy)-1-naphthaleneheptanoic acid.delta.-lactone.
The Product Monograph on lovastatin (i.e., mevinolin) by Merck, Sharp and Dohme (issued May 1988, DC 7,489,503) states that lovastatin is highly effective in the treatment of hypercholesterolemia. Further, at maximum doses, lovastatin produced a mean reduction of LDL cholesterol of 394 in two large multicenter control studies. In general, lovastatin was found to be well-tolerated in continuing extensive clinical trials as based on data from studies worldwide. Unfortunately, approximately 2% of patients were discontinued from therapy due to drug-related adverse effects in all clinical studies. The most frequently reported adverse side-effects were: headache (9.3%), flatus (6.4%), abdominal pain/cramps (5.7%), diarrhea (5.5%) and rash/pruritus (5.2%) (Id. at page 56).
Further, (Id.) the adverse experiences on treating patients with lovastatin in controlled clinical studies were GASTROINTESTINAL (constipation, diarrhea, dyspepsia, flatus, abdominal pain/cramps, heartburn and nausea); and MUSCULOSKELETAL (muscle cramps and myalgia); and NERVOUS SYSTEM/PSYCHIATRIC (dizziness, headache); SKIN (rash/pruritus); and SPECIAL SENSES (blurred vision and dysgeusia). Although some of these adverse experiences were also recorded when a placebo was administered, lovastatin consistently and definitely produced such adverse experience.
Also, (Id. at page 68), liver dysfunction from lovastatin can occur and approximately 0.5% of patients in clinical trials developed a myopathy.
Also, (page 68), there were eye dysfunctions indicated by a high prevalence of baseline lenticular opacities and during clinical trials, the appearance of new opacities was noted. The causal relationship of lovastatin to these opacities was not established. Of 431 patients, 34 had opacities at the final examination which occurred during 5-15 months after initiating therapy with lovastatin. However, existing opacities did not appear to increase.
In summary of the tolerability or the side effects from the clinical administration of lovastatin, this drug does have a variety of definite side effects some of which, particularly liver dysfunction, have justified discontinuation of therapy with lovastatin. Providing a method whereby the valuable group of HMG-CoA reductase inhibitors, such as lovastatin, could be used with a diminished risk for, or with the elimination of, the above-described physiological side effects, would provide a significant advance in the media acceptability and scope of treatable population for whom the use of such agents may be utilized.